Acyl- or acyloxymethyl-allopurinol prodrugs

ABSTRACT

Compounds of the formula Ia and Ib ##STR1## are prodrugs of allopurinol and have i.a. a much higher solubility in water and/or a higher lipophilicity than allopurinol, which makes such compounds useful for oral, parenteral and rectal administration to a warm-blooded animal such as a human. Such compounds will after administration be converted into allopurinol.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel transient prodrug forms ofallopurinol useful in the prevention and treatment of hyperuricemia, tomethods for preparing the prodrug forms, to pharmaceutical compositionscontaining such prodrug forms, and to methods for using the prodrugforms.

As employed in this application, the term "prodrug" denotes a derivativeof allopurinol which derivative, when administered to warm-bloodedanimals, e.g. humans, is converted into the proven drug, i.e.allopurinol.

The term "transient" indicates that the conversion of the prodrug formsproceeds in such a manner that the proven drug form (parent allopurinol)is released, and the remaining moieties split off remain nontoxic or aremetabolized so that nontoxic metabolic products are produced.

These novel prodrug forms of allopurinol are certain derivatives ofallopurinol which possess a desirable high lipophilicity and/or improvedaqueous solubility in comparison to the parent compound, allopurinol.

2. Description of the Prior Art

Allopurinol is a widely used agent for the treatment and prevention ofhyperuricemic states such as gout. Allopurinol and its main metaboliteoxipurinol lower the level of uric acid in plasma and urine byinhibiting xanthine oxidase, the enzyme catalyzing the oxidation ofhypoxanthine to xanthine and xanthine to uric acid (cf. e.g. Spector,1977; Elion, 1978). In addition to its use as prophylaxis against andtreatment of gout and other chronic hyperuricemic states allopurinol iscommonly used to prevent the development of hyperuricosuria that oftenresults from the rapid lysis of cells in patients with malignancies whoare undergoing treatment with cytotoxic drugs or radiation (cf. e.g.Elion, 1978).

Allopurinol is conventionally administered orally in the form oftablets. However, the development of nausea and vomiting among patientsundergoing cancer chemotherapy frequently precludes the use of oralpreparations in these patients. Consequently, a pharmaceutical andmedical need exists for allopurinol preparations useful for the controlof hyperurecemia in patients with neoplastic disease as well as in otherindividuals who are unable to take or retain oral medications.

Alternative means of administering allopurinol may be provided by theuse of injectable and rectal preparations.

However, since allopurinol is only slightly soluble in water (about 0.5mg/ml at 25° C.) acceptable injection preparations such as forintramuscular injection, are not available. Presently, it is onlypossible to deliver sufficient amounts of allopurinol parenterally byinfusion. The infusion fluids used contain the sodium salt ofallopurinol at a concentration of 0.5-1% and are strongly alkaline (pHabout 10.5-11.5); consequently, their administration may causethrombophlebitis or perivascular inflammation.

With respect to the rectal route of administering allopurinol recentstudies have demonstrated that this approach using allopurinol per se isnot a suitable and reliable mode of therapy (Chang et al., 1981;Appelbaum et al., 1980, 1982). It was shown in these studies thatvirtually no allopurinol or only very minute amounts (<5%) is absorbedfrom various suppository preparations administered rectally to man. Thisvery poor ability of allopurinol to be absorbed rectally can beattributed to the low lipophilicity of the drug combined with its poorwater solubility.

Although oral administration of allopurinol provides the attainment ofeffective serum concentrations the absorption of the compound is notcomplete. Thus, it has been reported that the absolute systemicbioavailability of oral allopurinol tablets in man are about 70%(Appelbaum et al., 1982) while another study (Elion et al., 1966)reported that about 20-25% of an oral dose is excreted in the stoolunchanged. The incomplete and variable absorption behaviour ofallopurinol can, like noted above for the rectal absorption, beattributed to the low water and lipid solubility of the drug.

Thus, it is quite obvious that a serious need exists for improved formsof allopurinol, which would be devoid of those disadvantages anddrawbacks that to date have characterized the parent drug, allopurinol.From the foregoing, it also appears that successful allopurinol prodrugsfor the preparation of pharmaceutically acceptable injectionpreparations should exhibit a high water-solubility at a physiologicallyacceptable pH. Furthermore, to provide an efficient, reliable and rapidabsorption upon rectal administration it also appears that successfulallopurinol prodrugs should possess both a desirable highwater-solubility and lipophilicity. In addition to these properties,successful prodrug derivatives should be capable of reverting to theactive allopurinol when absorbed into the bloodstream of a warm-bloodedanimal or when reaching the site of therapeutic activity of the parentdrug.

The only previously described prodrug types for allopurinol are someether derivatives (Hussain & Rytting, 1974), N-Mannich bases (Bundgaard& Johansen, 1981) and N-hydroxymethyl derivatives (Bansal et al., 1981).These compounds differ considerably from the compounds of the presentinvention. They are extremely unstable in aqueous solutions, arerelatively insoluble in water and lipid and apparently offer noadvantage over allopurinol with respect to bioavailability followingrectal or parenteral administration.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel prodrug forms ofallopurinol, useful for the prevention and treatment of hyperuricemicstates such as gout.

Another object of this invention is to provide novel prodrug forms ofallopurinol which prodrugs, or transient derivatives, owing to theirimproved lipid and/or water solubility, exhibit superior bioavailabilityover allopurinol per se, when administered rectally or orally.

A further object of the present invention is to provide novel transientprodrug forms of allopurinol which are characterized as being highlysoluble in water and hence are extremely useful as parenteral deliveryforms of allopurinol.

All foregoing objects are obtained with selected transient prodrug formsof allopurinol.

The ring structure named "allopurinol" exists in different tautomericforms: ##STR2##

Two of the tautomeric forms are drawn above and their systemic names aregiven, but in the present context, the term "allopurinol" encompassesall tautomeric forms of the ring system.

The invention relates to compounds of the formulas Ia or Ib ##STR3##wherein R₁ is a group of the formula II ##STR4## wherein R₃ is alkyl;phenyl; phenyl substituted with halogen, lower alkyl, hydroxy, loweralkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenylgroup may be substituted with halogen, lower alkyl, hydroxy, loweralkoxy, acetoxy or phenoxy; or phenyl-lower alkenyl in which the phenylgroup may be substituted with halogen, lower alkyl, hydroxy, loweralkoxy, acetoxy, or phenoxy; or R₃ is an aromatic 5- or 6-memberedheterocyclic ring containing one or two heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur; and A is a single bondor a group of the formula IIa ##STR5## wherein the carbon atom isattached to the nitrogen atom of the parent ring system, and wherein R₆and R₇ are the same or different and each represent hydrogen or have thesame meaning as R₃ as defined above;

or R₁ is a group of the formula III ##STR6## wherein R₈ and R₉ are thesame or different and each represent hydrogen or have the same meaningas R₃ as defined above; or R₈ and R₉ together with the adjacent nitrogenfrom a 5- or 6-membered heterocyclic ring, which in addition to thenitrogen may contain one or two further heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur; Y is a single bond or agroup of the formula IIIa ##STR7## wherein n is an integer from 1 to 5;and A, R₆, and R₇ are as defined above;

or R₁ is a group of the formula IV ##STR8## wherein A is as definedabove and R₃ ' has the same meaning as R₃ defined above, with theproviso that R₃ is not ethyl when A is a bond;

or R₁ is a group of the formula VI ##STR9## wherein R₁₀ is a mono- orpolyhalogenated lower alkyl group and A is as defined above;

or R₁ is a group of the formula VII ##STR10## wherein n and A are asdefined above, and R₁₃ is hydroxy or a group of the formula --NR₈ R₉wherein R₈ and R₉ are as defined above;

or R₁ is a group of the formula IX ##STR11## wherein R₆ and R₇ are asdefined above; R₂ is any of the groups II, III, IV, VI, and VII asdefined above with the proviso that A solely is the group IIa as definedabove;

and R₅ is hydrogen or has the same meaning as R₂ as defined above,

and salts thereof.

In the present context, the term "alkyl" designates C₁₋₈ alkyl which maybe straight or branched, such as methyl, ethyl, propyl, isopropyl,butyl, tert.butyl, pentyl, hexyl, heptyl, or octyl. Among the alkylgroups, lower alkyl groups are preferred. The term "lower alkyl"designates C₁₋₄ alkyl which may be straight or branched, such as methyl,ethyl, propyl, isopropyl, butyl, or tert.butyl. The term "phenyl-loweralkyl" designates a lower alkyl group (as herein defined) which, inturn, is substituted with a phenyl group. Preferred phenyl-lower alkylare benzyl, 1- and 2-phenylethyl, 1-, 2-, and 3-phenylpropyl, and1-methyl-1-phenylethyl The term "lower alkoxy" designates oxy to which alower alkyl group is attached as defined above; preferred alkoxy groupsare methoxy and ethoxy. The term "halogen" designates F, Cl, Br, or l;Cl is preferred. The term "phenyl-lower alkenyl" designates a C₂₋₅-monounsaturated aliphatic hydrocarbon group which may be straight orbranched, such as propenyl, butenyl or pentenyl, and which in turn issubstituted with a phenyl group. Preferred phenyl-lower alkenyl groupsare phenyl-substituted propen(2)-yl optionally substituted with methylor ethyl, such as 3-phenylpropen(2)-yl (both E and Z forms),2-methyl-3-phenylpropen(2)-yl (both E and Z forms), and3-phenylbuten(2)-yl (both E and Z forms). Where phenyl groups aresubstituted with e.g. halogen, lower alkyl, hydroxy, lower alkoxy,acetoxy or phenoxy, they may be mono-, di-, or tri-substituted, and whenthey are di-, or tri-substituted, the substituents may be the same ordifferent. The term "polyhalogenated lower alkyl" designates lower alkyl(as defined above) substituted with two or more halogen atoms, which maybe the same or different. A preferred example of polyhalogenated loweralkyl is trichloromethyl. When, in the formula II, R₃ is an aromatic 5-or 6-membered heterocyclic ring containing 1 or 2 hetero atoms selectedfrom the group consisting of nitrogen, oxygen, and sulphur, this may,for instance, be 2-, 3-, or 4-pyridinyl, 2-, or 3-thienyl, 2-, 4-, or5-thiazolyl, 2-, 4-, or 5-oxazolyl, 2-imidazolyl, 5-isoxazolyl,5-isothiazolyl, 2-furanyl, 2-, or 5-pyrimidinyl, 5-[1,3]-oxazinyl, or5-[1,3]-thiazinyl. When, in the formula III, R₈ and R₉ together with theadjacent nitrogen atom form a 5- or 6-membered heterocyclic ring whichin addition to the nitrogen may contain 1 or 2 further hetero atomsselected from the group consisting of nitrogen, oxygen, and sulphur, itmay, for instance, be 1-piperidinyl, 1-imidazolyl, 1-pyrazolyl,morpholinyl, 1-piperazinyl, and thiomorpholinyl.

The salts of the compounds of the formulas Ia or Ib include anypharmaceutically acceptable acid addition salt. This term as used hereingenerally includes the non-toxic acid addition salts of compounds of theformulas Ia or Ib, formed with non-toxic inorganic or organic acids. Forexample, the salts include salts with inorganic acids, such ashydrochloric, hydrobromic, sulphuric, sulphamic, nitric, phosphoric andthe like; and the salts with organic acids such as acetic, propionic,succinic, fumaric, maleic, tartaric, citric, glycolic, stearic, lactic,malic, pamoic, ascorbic, phenylacetic, glutamic, benzoic, salicylic,sulphonic, sulphanilic, and the like.

When one or more asymmetric carbon atoms are present in the side chains,it is understood that the present invention also encompasses alldiastereomers or enantiomers, or mixtures thereof. Examples of isomersare D-, L-, and DL-forms.

The compound of formula Ia wherein R₁ is ethyloxycarbonyl (R₁ is a groupof formula IV wherein A is a bond and R₃ ' is ethyl) and R₅ is hydrogenis described in the literature (Bergmann et al, 1979). However, thisreference merely teaches a method for preparing this compound and doesnot disclose or indicate any utility of the compound, nor any propertiesof the compound that might indicate its utility as a prodrug.

In another aspect the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier or excipient and acompound of the formulas I'a or Ib ##STR12## wherein R₁ is a group ofthe formula II ##STR13## wherein R₃ is alkyl; phenyl; phenyl substitutedwith halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy;phenyl-lower alkyl in which the phenyl group may be substituted withhalogen, lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; orphenyl-lower alkenyl in which the phenyl group may be substituted withhalogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; or R₃is an aromatic 5- or 6-membered heterocyclic ring containing one or twoheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur; and A is a single bond or a group of the formula IIa ##STR14##wherein the carbon atom is attached to the nitrogen atom of the parentring system, and wherein R₆ and R₇ are the same or different and eachrepresent hydrogen or have the same meaning as R₃ as defined above;

or R₁ is a group of the formula III ##STR15## wherein R₈ and R₉ are thesame or different and each represent hydrogen or have the same meaningas R₃ as defined above; or R₈ and R₉ together with the adjacent nitrogenform a 5- or 6-membered heterocyclic ring, which in addition to thenitrogen may contain one or two further heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur; Y is a single bond or agroup of the formula IIIa ##STR16## wherein n is an integer from 1 to 5;and A, R₆, and R₇ are as defined above;

or R₁ is a group of the formula IV ##STR17## wherein R₃ and A are asdefined above; or R₁ is a group of the formula VI ##STR18## wherein R₁₀is a mono- or polyhalogenated lower alkyl group and A is as definedabove;

or R₁ is a group of the formula VII ##STR19## wherein n and A are asdefined above, and R₁₃ is hydroxy or a group of the formula --NR₈ R₉wherein R₈ and R₉ are as defined above;

or R₁ is a group of the formula IX ##STR20## wherein R₆ and R₇ are asdefined above; R₂ is any of the groups II, III, IV, VI, and VII asdefined above with the proviso that A solely is the group IIa as definedabove;

and R₅ is hydrogen or has the same meaning as R₂ as defined above,

and salts thereof.

In another aspect the present invention also concerns a method forpreparing the above mentioned compositions comprising combining apharmaceutically acceptable carrier or excipient with a compound of theformulas I'a or Ib.

In a further aspect the invention also concerns a method for preparingcompounds of the formulas I'a or Ib.

In yet another aspect the invention concerns a method for treating andpreventing hyperuricemic states comprising administering an amounteffective in lowering the level of uric acid, of a compound of thepresent invention optionally in a pharmaceutical composition asdescribed above, to warm-blooded animals including humans.

DETAILED DESCRIPTION OF THE INVENTION

As examples of compounds of formula Ia or I'a may be mentioned compoundsin which R₅ is as defined above, and R₁ is one of the following groups("groups a");

Acetyl

Propionyl

Butyryl

Isobutyryl

Valeryl

Benzoyl

4-Methylbenzoyl

2,4-Dimethylbenzoyl

4-Chlorobenzoyl

4-Methoxybenzoyl

3,4-Dimethoxybenzoyl

4-Hydroxybenzoyl

2-Hydroxylbenzoyl

4-Acetoxybenzoyl

2-Acetoxybenzoyl

4-Phenoxybenzoyl

Phenylacetyl

4-Chlorophenylacetyl

3-Phenylpropionyl

Nicotinoyl

Isonicotinoyl

Picolyl

2-Thienoyl

Cinnamoyl

4-Methylcinnamoyl

4-Chlorocinnamoyl

Glycyl

N,N-Dimethylglycyl

N,N-Diethylglycyl

N,N-Dipropylglycyl

N-Methylglycyl

N-Ethylglycyl

N-Propylglycyl

Alanyl

N,N-Dimethylalanyl

N,N-Diethylalanyl

Leucyl

Norleucyl

Norvalyl

Valyl

Phenylalanyl

3-(N,N-Dimethylamino)propionyl

4-(N,N-Dimethylamino)butyryl

4-(N,N-Diethylamino)butyryl

5-(N,N-Dimethylamino)valeryl

N,N-Dimethylphenylalanyl

Methoxycarbonyl

Ethoxycarbonyl

Butoxycarbonyl

Hexyloxycarbonyl

Phenoxycarbonyl

4-Chlorophenoxycarbonyl

4-Methoxyphenoxycarbonyl

Benzyloxycarbonyl

Carbamoyl

N-Methylcarbamoyl

N-Ethylcarbamoyl

N-Butylcarbamoyl

N-Phenylcarbamoyl

N,N-Dimethylcarbamoyl

Chloroacetyl

Bromoacetyl

Trichloroacetyl

Trifluoroacetyl

2-Chloropropionyl

2-Bromopropionyl

Succinyl

Formyloxymethyl

Acetyloxymethyl

Propionyloxymethyl

Butyryloxymethyl

Isobutyryloxymethyl

Pivaloyloxymethyl

Valeryloxymethyl

Benzoyloxymethyl

4-Chlorobenzoyloxymethyl

4-Methylbenzoyloxymethyl

2,4-Dimethylbenzoyloxymethyl

4-Methoxybenzoyloxymethyl

3,4-Dimethoxybenzoyloxymethyl

4-Hydroxybenzoyloxymethyl

2-Hydroxybenzoyloxymethyl

4-Acetoxybenzoyloxymethyl

2-Acetoxybenzoyloxymethyl

4-Phenoxybenzoyloxymethyl

Phenylacetyloxymethyl

3-Phenylpropionyloxymethyl

Nicotinoyloxymethyl

Isonicotinoyloxymethyl

Picolyloxymethyl

1-(Acetyloxy)ethyl

1-(Acetyloxy)propyl

1-(Butyryloxy)ethyl

1-(Butyryloxy)propyl

(Acetyloxy)(phenyl)methyl

Glycyloxymethyl

N,N-Dimethylglycyloxymethyl

1-(N,N-Dimethylglycyloxy)ethyl

N,N-Diethylglycyloxymethyl

1-(N,N-Diethylglycyloxy)ethyl

N,N-Dipropylglycyloxymethyl

1-(N,N-Dipropylglycyloxy)ethyl

N-Methylglycyloxymethyl

N-Ethylglycyloxymethyl

N-Propylglycyloxymethyl

Alanyloxymethyl

N,N-Dimethylalanyloxymethyl

1-(N,N-Dimethylalanyloxy)ethyl

N,N-Diethylalanyloxymethyl

1-(N,N-Diethylalanyloxy)ethyl

Leucyloxymethyl

N,N-Dimethylleucyloxymethyl

Norleucyloxymethyl

Valyloxymethyl

Norvalyloxymethyl

Phenylglycyloxymethyl

Phenylalanyloxymethyl

N,N-Dimethylphenylalanyloxymethyl

N,N-Diethylphenylalanyloxymethyl

Methoxycarbonyloxymethyl

Ethoxycarbonyloxymethyl

Phenoxycarbonyloxymethyl

Benzyloxycarbonyloxymethyl

Trifluoroacetyloxymethyl

Chloroacetyloxymethyl

Succinyloxymethyl

3-(N,N-Diethylcarbamoyl)propionyloxymethyl

Phosphonooxymethyl

and salts thereof.

Of the compounds in which R₅ is different from hydrogen, preferredcompounds of the formulas Ia or I'a are compounds in which R₁ and R₅ arethe same, since such compounds are generally easier to prepare.

Among these compounds (i.e. R₁ and R₅ are the same) more preferredcompounds are compounds wherein R₁ and R₅ are groups of the formulas IIor III as defined above, wherein A is a group of formula IIa, and Y is agroup of formula IIIa; and salts thereof.

Examples of such compounds are compounds in which R₁ and R₅ are one ofthe following groups ("groups b"):

Formyloxymethyl

Acetyloxymethyl

Propionyloxymethyl

Butyryloxymethyl

Isobutyryloxymethyl

Pivaloyloxymethyl

Valeryloxymethyl

Benzoyloxymethyl

4-Chlorobenzoyloxymethyl

2,4-Dimethylbenzoyloxymethyl

4-Methoxybenzoyloxymethyl

3,4-Dimethoxybenzoyloxymethyl

4-Hydroxybenzoyloxymethyl

2-Hydroxybenzoyloxymethyl

4-Acetoxybenzoyloxymethyl

2-Acetyloxybenzoyloxymethyl

4-Phenoxybenzoyloxymethyl

Phenylacetyloxymethyl

3-Phenylpropionyloxymethyl

Nicotinoyloxymethyl

Isonicotinoyloxymethyl

Picolyloxymethyl

1-(Acetyloxy)ethyl

1-(Acetyloxy)propyl

1-(Butyryloxy)ethyl

1-(Butyryloxy)propyl

(Acetyloxy)(phenyl)methyl

Glycyloxymethyl

1-(N,N-Dimethylglycyloxy)ethyl

N,N-Diethylglycyloxymethyl

1-(N,N-Diethylglycyloxy)ethyl

N,N-Dipropylglycyloxymethyl

1-(N,N-Dipropylglycyloxy)ethyl

N-Methylglycyloxymethyl

N-Ethylglycyloxymethyl

N-Propylglycyloxymethyl

Alanyloxymethyl

N,N-Dimethylalanyloxymethyl

1-(N,N-Dimethylalanyloxy)ethyl

N,N-Diethylalanyloxymethyl

1-(N,N-Diethylalanyloxy)ethyl

Leucyloxymethyl

N,N-Dimethylleucyloxymethyl

Norleucyloxymethyl

Valyloxymethyl

Norvalyloxymethyl

Phenylglycyloxymethyl

Phenylalanyloxymethyl

N,N-Dimethylphenylalanyloxymethyl

N,N-Diethylphenylalanyloxymethyl

and salts thereof.

Other more preferred compounds of the formulas Ia or I'a are compoundswherein R₅ is hydrogen and R₁ is a group of the formula II, III, IV, VI,VII or IX; and salts thereof.

Examples of such compounds are compounds wherein R₅ is hydrogen and R₁is a group selected from the groups a specified above.

Among these compounds (i.e. R₅ is hydrogen) still more preferredcompounds are compounds wherein R₁ is a group of the formulas II, IIIwherein Y is a group of formula IIIa, or VII.

Examples of such compounds are compounds wherein R₅ is hydrogen and R₁is one of the following groups ("groups c"):

Acetyl

Propionyl

Butyryl

Isobutyryl

Valeryl

Benzoyl

4-Methylbenzoyl

2,4-Dimethylbenzoyl

4-Chlorobenzoyl

4-Methoxybenzoyl

3,4-Dimethoxybenzoyl

4-Hydroxybenzoyl

2-Hydroxybenzoyl

4-Acetoxybenzoyl

2-Acetoxybenzoyl

4-Phenoxybenzoyl

Phenylacetyl

4-Chlorophenylacetyl

3-Phenylpropionyl

Nicotinoyl

Isonicotinoyl

Picolyl

2-Thienoyl

Cinnamoyl

4-Methylcinnamoyl

4-Chlorocinnamoyl

Glycyl

N,N-Dimethylglycyl

N,N-Diethylglycyl

N,N-Dipropylglycyl

N-Methylglycyl

N-Ethylglycyl

N-Propylglycyl

Alanyl

N,N-Dimethylalanyl

N,N-Diethylalanyl

Leucyl

Norleucyl

Norvalyl

Valyl

Phenylalanyl

3-(N,N-Dimethylamino)propionyl

4-(N,N-Dimethylamino)butyryl

4-(N,N-Diethylamino)butyryl

5-(N,N-Dimethylamino)valeryl

N,N-Dimethylphenylalanyl

Succinyl

Formyloxymethyl

Acetyloxymethyl

Propionyloxymethyl

Butyryloxymethyl

Isobutyryloxymethyl

Pivaloyloxymethyl

Valeryloxymethyl

Benzoyloxymethyl

4-Chlorobenzoyloxymethyl

4-Methylbenzoyloxymethyl

2,4-Dimethylbenzoyloxymethyl

4-Methoxybenzoyloxymethyl

3,4-Dimethoxybenzoyloxymethyl

4-Hydroxybenzoyloxymethyl

2-Hydroxybenzoyloxymethyl

4-Acetoxybenzoyloxymethyl

2-Acetoxybenzoyloxymethyl

4-Phenoxybenzoyloxymethyl

Phenylacetyloxymethyl

3-Phenylpropionyloxymethyl

Nicotinoyloxymethyl

Isonicotinoyloxymethyl

Picolyloxymethyl

1-(Acetyloxy)ethyl

1-(Acetyloxy)propyl

1-(Butyryloxy)ethyl

1-(Butyryloxy)propyl

(Acetyloxy)(phenyl)methyl

Glycyloxymethyl

N,N-Dimethylglycyloxymethyl

1-(N,N-Dimethylglycyloxy)ethyl

N,N-Diethylglycyloxymethyl

1-(N,N-Diethylglycyloxy)ethyl

N,N-Dipropylglycyloxymethyl

1-(N,N-Dipropylglycyloxy)ethyl

N-Methylglycyloxymethyl

N-Ethylglycyloxymethyl

N-Propylglycyloxymethyl

Alanyloxymethyl

N,N-Dimethylalanyloxymethyl

1-(N,N-Dimethylalanyloxy)ethyl

N,N-Diethylalanyloxymethyl

1-(N,N-Diethylalanyloxy)ethyl

Leucyloxymethyl

N,N-Dimethylleucyloxymethyl

Norleucyloxymethyl

Valyloxymethyl

Norvalyloxymethyl

Phenylglycyloxymethyl

Phenylalanyloxymethyl

N,N-Dimethylphenylalanyloxymethyl

N,N-Diethylphenylalanyloxymethyl

Succinyloxymethyl

3-N,N-Diethylcarbamoyl)propionyloxymethyl

and salts thereof.

Still more preferred compounds of the formula Ia are compounds whereinR₅ is hydrogen and R₁ is a group of the formulas II, III wherein Y is agroup of formula IIIa, or VII, wherein A in all the formulas mentionedis a group of formula IIa.

Examples of such compounds are compounds wherein R₅ is hydrogen and R₁is one of the groups b specified above.

Even more preferred compounds of the formula Ia are compounds wherein R₅is hydrogen and R₁ is a group of the formula III wherein A is a group offormula IIa and Y is a group of formula IIIa.

Examples of such compounds are compounds wherein R₅ is hydrogen and R₁is one of the following groups ("groups d"):

Glycyloxymethyl

N,N-Dimethylglycyloxymethyl

1-(N,N-Dimethylglycyloxy)ethyl

N,N-Diethylglycyloxymethyl

1-(N,N-Diethylglycyloxy)ethyl

N,N-Dipropylglycyloxymethyl

1-(N,N-Dipropylglycyloxy)ethyl

N-Methylglycyloxymethyl

N-Ethylglycyloxymethyl

N-Propylglycyloxymethyl

Alanyloxymethyl

N,N-Dimethylalanyloxymethyl

1-(N,N-Dimethylalanyloxy)ethyl

N,N-Diethylalanyloxymethyl

1-(N,N-Diethylalanyloxy)ethyl

Leucyloxymethyl

N,N-Dimethylleucyloxymethyl

Norleucyloxymethyl

Valyloxymethyl

Norvalyloxymethyl

Phenylglycyloxymethyl

Phenylalanyloxymethyl

N,N-Dimethylphenylalanyloxymethyl

N,N-Diethylphenylalanyloxymethyl

and salts thereof.

Particularly preferred compounds of the formula Ia are compounds inwhich R₅ is hydrogen and R₁ is N,N-dimethylglycyloxymethyl,N,N-diethylglycyloxymethyl, N,N-dipropylglycyloxymethyl,N,N-dimethylalanyloxymethyl, N,N-diethylalanyloxymethyl,phenylalanyloxymethyl, phenylglycyloxymethyl, or leucyloxymethyl; andsalts thereof.

Among the compounds of the formula Ib preferred compounds are compoundsin which R₂ and R₅ are the same. Examples of such compounds arecompounds, in which R₂ and R₅ are groups selected from the groups bspecified above.

Even more preferred compounds of the formula Ib are compounds in whichR₂ and R₅ are the same and R₂ and R₅ are groups of the formula III asdefined above wherein A is a group of formula IIa and Y is a group offormula IIIa.

Examples of such compounds are compounds wherein R₅ and R₂ are the sameand are selected from the groups d specified above; and salts thereof.

Other very preferred compounds of the formula Ib are compounds whereinR₅ is hydrogen and R₂ is a group of the formula II wherein A is a groupof formula IIa.

Examples of such compounds are compounds wherein R₅ is hydrogen and R₂is one of the following groups ("groups e"):

Formyloxymethyl

Acetyloxymethyl

Propionyloxymethyl

Butyryloxymethyl

Isobutyryloxymethyl

Pivaloyloxymethyl

Valeryloxymethyl

Benzoyloxymethyl

4-Chlorobenzoyloxymethyl

4-Methylbenzoyloxymethyl

2,4-Dimethylbenzoyloxymethyl

4-Methoxybenzoyloxymethyl

3,4-Dimethoxybenzoyloxymethyl

4-Hydroxybenzoyloxymethyl

4-Acetoxybenzoyloxymethyl

4-Phenoxybenzoyloxymethyl

Phenylacetyloxymethyl

3-Phenylpropionyloxymethyl

Nicotinoyloxymethyl

Isonicotinoyloxymethyl

Picolyloxymethyl

1-(Acetyloxy)ethyl

1-(Acetyloxy)propyl

1-(Butyryloxy)ethyl

1-(Butyryloxy)propyl

(Acetyloxy)(phenyl)methyl

and salts thereof.

Specific examples of preferred compounds of formula Ia are:

1-(Acetyloxymethyl)allopurinol

1-(Propionyloxymethyl)allopurinol

1-(Butyryloxymethyl)allopurinol

1-(Glycyloxymethyl)allopurinol

1-(DL-Alanyloxymethyl)allopurinol

1-(L-Alanyloxymethyl)allopurinol

1-(N,N-Dimethylglycyloxymethyl)allopurinol

1-(N,N-Diethylglycyloxymethyl)allopurinol

1-(N,N-Dipropylglycyloxymethyl)allopurinol

1-(DL-N,N-Dimethylalanyloxymethyl)allopurinol

1-(L-N,N-Dimethylalanyloxymethyl)allopurinol

1-(DL-N,N-Diethylalanyloxymethyl)allopurinol

1-(L-N,N-Diethylalanyloxymethyl)allopurinol

1-(DL-Phenylalanyloxymethyl)allopurinol

1-(L-Phenylalanyloxymethyl)allopurinol

1-(DL-Phenylglycyloxymethyl)allopurinol

1-(L-Phenylglycyloxymethyl)allopurinol

1-(DL-Leucyloxymethyl)allopurinol

1-(L-Leucyloxymethyl)allopurinol

1-(DL-Norleucyloxymethyl)allopurinol

1-(L-Norleucyloxymethyl)allopurinol

1-(DL-Norvalyloxymethyl)allopurinol

1-(L-Norvalyloxymethyl)allopurinol

1-(DL-Valyloxymethyl)allopurinol

1-(L-Valyloxymethyl)allopurinol

1-(DL-N,N-Dimethylphenylalanyloxymethyl)allopurinol

1-(DL-N,N-Diethylphenylalanyloxymethyl)allopurinol

and salts thereof.

Specific examples of preferred compounds of formula Ib are:

2-(Acetyloxymethyl)allopurinol

2-(Propionyloxymethyl)allopurinol

2-(Butyryloxymethyl)allopurinol

2-(Benzoyloxymethyl)allopurinol

2,5-bis(Acetyloxymethyl)allopurinol

2,5-bis(Propionyloxymethyl)allopurinol

2,5-bis(Butylryloxymethyl)allopurinol

2,5-bis(Benzoyloxymethyl)allopurinol

2,5-bis(N,N-Dimethylglycyloxymethyl)allopurinol

2,5-bis(N,N-Diethylglycyloxymethyl)allopurinol

2,5-bis(N,N-Dipropylglycyloxymethyl)allopurinol

2,5-bis(DL-N,N-Dimethylalanyloxymethyl)allopurinol

2,5-bis(DL-N,N-Diethylalanyloxymethyl)allopurinol

2,5-bis(DL-Phenylalanyloxymethyl)allopurinol

2,5-bis(L-Phenylalanyloxymethyl)allopurinol

2,5-bis(L-Leucyloxymethyl)allopurinol

and salts thereof.

Specific examples of especially preferred compounds are:

1-(Butyryloxymethyl)allopurinol,

1-(N,N-dimethylglycyloxymethyl)allopurinol,

1-(N,N-diethylglycyloxymethyl)allopurinol,

1-(N,N-dipropylglycyloxymethyl)allopurinol,

1-(DL-N,N-dimethylalanyloxymethyl)allopurinol,

1-(DL-N,N-diethylalanyloxymethyl)allopurinol,

1-(L-phenylalanyloxymethyl)allopurinol,

1-(L-leucyloxymethyl)allopurinol,

1-(L-valyloxymethyl)allopurinol, and

1-(DL-N,N-dimethylphenylalanyloxymethyl)allopurinol,

and salts thereof.

Dose and dosage forms

The compounds of the present invention are conveniently administered towarm-blooded animals, e.g. humans, via rectal, oral or parenteral dosageforms. The dose of the compounds of the present invention administeredto warm-blooded animals, e.g. humans, (either as a single dose, a dailydose, or other time-presented doses) will, of course, depend on therequirements of the individual under treatment. The dosage administered,is, therefore, not subject to specific limits. However, the dose of anycompound of the formulas I'a or Ib will usually be an amount, which--ona molar basis--is equivalent to the amount of allopurinol necessary toachieve the desired pharmacological or physiological effect. Generally,the single medical dose for warm-blooded animals, which include humansand primates, will be in the range of approximately 25-1000 mgallopurinol equivalents. For humans the daily dose is generally in therange of 300-600 mg allopurinol equivalents regardless of administrationform. The daily dose may be administered in 1-3 single doses.

The compounds of the formulas I'a or Ib may be administered in the formof tablets, capsules, suspensions, emulsions, solutions, injectables,suppositories, enemas, various drug delivery devices and in othersuitable form. The route of administration may be orally, parenterallyor rectally. The formulation and preparation of any of this broadspectrum of dosage forms into which the subject prodrugs can bedispensed is well-known to those skilled in the art of pharmaceuticalformulation. Specific information can, however, be found in the textentitled "Remington's Pharmaceutical Sciences", Sixteenth Edition, 1980.

In a typical preparation for oral administration, e.g. tablet orcapsule, any one of the compounds of the present invention in apharmacologically effective amount is combined with any oral nontoxicpharmaceutically acceptable inert carrier such as lactose, starch andmicrocrystalline cellulose. Additionally, when required, suitablebinders (e.g. gelatin), lubricants (e.g. talc or magnesium stearate) anddisintegrating agents (e.g. starch or various cellulose derivatives) areincluded.

Similarly, in a typical formulation for parenteral application(intravenous, intramuscular, subcutaneous or the like), any of thehighly water-soluble compounds of the present invention, such as1-(N,N-dimethylglycyloxymethyl)allopurinol hydrochloride is dissolved insterile water in a given concentration and sterilized by e.g. membranefiltration, or radiation. The pH of the solution may, if necessary, beadjusted with e.g. hydrochloric acid, sodium hydroxide or a suitablebuffer, and a suitable preservative may optionally be added. Similarly,agents like sodium chloride may be added in order to adjust the tonicityof the solution. A suitable parenteral preparation may also consist ofthe compound formulated as a sterile, solid substance distributed ininjection vials. Before dispensing, water for injection is added todissolve the compound.

For the rectal application of the allopurinol prodrugs of thisinvention, typical dosage forms include suppositories (emulsion andsuspension types), rectal gelatin capsules (solutions and suspensions),and enemas or micro-enemas (solutions and suspensions). Thus, in atypical suppository formulation, any one of the compounds of thisinvention is combined with any pharmaceutically acceptable suppositorybase such as cocoa butter, esterified fatty acids (C₁₀ -C₁₈),glycerinated gelatin, and various water-soluble or dispersible baseslike polyethylene glycols and polyoxyethylene sorbitan fatty acidesters. Various additives like salicylates or surfactant materials maybe incorporated. Enemas or micro-enemas of the solution type may simplybe prepared by dissolving the water-soluble prodrugs of this inventionin water or in water containing e.g. 0.5% of methylcellulose or anotherviscosity-increasing agent.

The novel and useful allopurinol prodrugs of the invention are alsoadaptable for administration to warm-blooded animals from various noveldrug delivery systems such as gastrointestinal drug delivery devices andrectally applied osmotic delivery devices, wherein the delivery deviceis manufactured from naturally occurring or synthetic polymericmaterials. Specific information about osmotic delivery systems forrectal application can be found in De Leede & De Boer (1981) and DeLeede et al. (1982).

From the foregoing description, it is obvious that due to the muchimproved water-solubility of selected members of the claimed prodrugsover allopurinol per se and derivatives of the prior art, superiorparenteral formulation and administration is achieved. Similarly, anexceptionally improved rectal bioavailability is achieved owing to theincreased water-solubility and/or lipophilicity of the subjectcompounds.

The compounds of the present invention may be prepared by variousmethods.

One method (a) for preparing compounds of the formula I'a wherein R₅ ishydrogen and A is a bond comprises

reacting allopurinol with a compound of the formula XI ##STR21## whereinR₁₂ has the same meaning as R₃ as defined above; R₁₂ is a group of theformula III' ##STR22## wherein Y is as defined above, and R₈ ' and R₉ 'have the same meaning as R₈ and R₉ as defined above; or R₈ ' or R₉ ' arean amino protecting group;

R₁₂ is a group of the formula IV'

    R.sub.3 --O--                                              IV'

wherein R₃ is as defined above;

R₁₂ has the same meaning as R₁₀ as defined above;

or R₁₂ is a group of the formula VII' ##STR23## wherein n is as definedabove, and R₁₃ is hydroxy or a group of the formula --NR₈ R₉ wherein R₈and R₉ are as defined above; and Z is a leaving group; and then, if anamino protecting group has been used, removing the protecting group.

Another method (b) for preparing compounds of the formula I'a wherein R₅is hydrogen or compounds of formula Ib wherein R₂ and R₅ are the same,and wherein A is --CH₂ --, comprises

reacting 1-hydroxymethylallopurinol or 2,5-dihydroxymethylallopurinolwith a compound of the formula XI as shown above and wherein R₁₂ is asdefined above; and then, if an amino protecting group has been used,removing the protecting group.

A method (c) for preparing compounds of formulas I'a or Ib whereineither R₅ is hydrogen or R₁ and R₅ are the same or R₂ and R₅ are thesame, comprises

reacting allopurinol with a compound of the formula XII ##STR24##wherein R₆, R₇, R₁₂ and Z are as defined above, and then, if an aminoprotecting group has been used, removing the protecting group.

Other methods (d) and (e) for preparing compounds of the formula I'awherein R₅ is different from hydrogen are contemplated.

Method (d) comprises

reacting a compound of the formula XIII ##STR25## wherein R₁ is asdefined above in connection with formula I'a, with a compound of theformula XII, wherein R₆, R₇, R₁₂, and Z are as defined; and then, if anamino protecting group has been used, removing the protecting group.

Method (e) comprises

reacting a compound of the formula XIV ##STR26## wherein R₁ is asdefined above in connection with formula I'a with a compound of theformula XI as shown above, wherein R₁₂ and Z are as defined above; andthen, if an amino protecting group has been used, removing theprotecting group.

A method (f) for preparing compounds of the formula Ib wherein R₅ isdifferent from hydrogen is contemplated.

Method (f) comprises

reacting a compound of the formula XV ##STR27## wherein R₂ is as definedabove, with a compound of the formula XII, wherein R₆, R₇, R₁₂, and Zare as defined above; and then, if an amino protecting group has beenused, removing the protecting group.

Another method (g) for preparing compounds of the formula I'a wherein R₅is hydrogen or compounds of formula Ib wherein R₂ and R₅ are the samecomprises reacting allopurinol, 1-hydroxymethylallopurinol, or2,5-dihydroxymethylallopurinol with a compound of the formula V"

    R.sub.3--N═C═O                                     V"

wherein R₃ is as defined above.

Still another method (h) for preparing compounds of the formula I'awherein R₅ is hydrogen or compounds of formula Ib wherein R₂ and R₅ arethe same comprises reacting allopurinol, 1-hydroxymethylallopurinol, or2,5-dihydroxymethylallopurinol with a compound of the formula VII"##STR28## wherein n is as defined above.

A method (i) for preparing compounds of the formula I'a wherein R₅ ishydrogen or compounds of formula Ib wherein R₂ and R₅ are the samecomprises reacting a compound of the formula XVI ##STR29## wherein R₈and R₉ are as defined above, with a compound of formula XVII ##STR30##or with a compound of formula XVIII ##STR31## or with a compound offormula XIX ##STR32## wherein n and Z are as defined above.

A method (j) for preparing compounds of the formula I'a wherein R₁ is##STR33## and R₅ is hydrogen is contemplated.

Method (j) comprises

(1) hydrogenation of the corresponding dibenzyl phosphate, or

(2) hydrolysis of the corresponding 2-cyanoethyl phosphate, or

(3) reacting 1-hydroxymethylallopurinol with pyrophosphoryltetrachloride followed by hydrolysis.

In the present context the name 1-hydroxymethylallopurinol designatesthe compound1-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one andtautomeric forms hereof, and the name 2,5-dihydroxymethylallopurinoldesignates2,5-[bis(hydroxymethyl)]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand tautomeric forms hereof. The synthesis of both compounds have beendescribed (Bansal et al (1981)). It is noted that in this reference, thecompound which in the present context is designated2,5[bis(hydroxymethyl)]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inthe cited reference is designated as the corresponding1,5-[bis(hydroxymethyl)]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one.However, according to analyses performed by the present applicants, thecompound prepared according to the teaching of the reference is believedin fact to be the 2,5-compound, for which reason the compound has beendesignated as the 2,5-compound above. However, as it can still not beconcluded with certainty that the compound is indeed the 2,5-compound,the above designation should be understood as covering alternatively the1,5-compound provided the synthesis described in the reference is infact conclusively found to result in the 1,5-compound.

The assignment of the actual positions of the substituents is based onthe UV and NMR spectra according to the principles set forth in Bergmanet al (1979).

As examples of leaving groups Z may be mentioned chlorine, bromine andiodine. Group Z may also be an acyloxy group, i.e. the reacting compoundof e.g. formula XI may be an anhydride or a mixed anhydride. When Z ishydroxy a dehydrating agent (e.g. a carbodiimide) has to be present andnormally, a sulfonic acid is added to suppress side-reactions.

The term "amino protecting group" designates groups readily removable byhydrolysis or hydrogenation. As examples of such amino protecting groupsmay be mentioned methyloxycarbonyl, ethyloxycarbonyl,tert.butyloxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trityl, or thelike.

Methods (a), (b) and (e) are performed under essentially the sameconditions. The reaction is carried out without a solvent or in asolvent (e.g. pyridine, N,N-dimethylformamide, dimethyl sulfoxide,methylene chloride, or the like). Usually a base (e.g. a tertiary amine,pyridine, potassium carbonate, or the like) has to be present. Thetemperature during the reaction is usually between 0° C. and the boilingpoint of either the solvent or the boiling point of one of thereactants. The reaction time is normally from 1 to 96 hours.

Methods (c), (d) and (f) are performed under the same conditions. Theleaving group Z will often be chlorine, bromine or iodine. The reactionis carried out preferably in a polar solvent (e.g. acetone,N,N-dimethylformamide, dimethylsulfoxide, or the like) and in thepresence of a base (a metal carbonate, a tertiary amine, or the like).The reaction temperature will normally be between 0° C. and 100° C. andthe reaction time from 1 to 96 hours. In method (c) a mixture ofcompounds are normally obtained. Dependent on the reaction conditionsand on the number of equivalents of the compound of the formula XII usedas reagent, compounds with a substituent R₂ alone (i.e. R₅ is hydrogen)and compounds in which R₂ and R₅ are the same, are obtained. Asby-products, compounds with a substituent R₁ alone and compounds inwhich R₁ and R₅ are the same are also obtained. The mixture of compoundscan be separated by manners known per se, i.e. crystallization or columnchromatography.

Method (g) is performed in an inert solvent (e.g. toluene, methylenechloride, N,N-dimethylformamide, or the like). The reaction is carriedout at a temperature from 0° C. to the boiling point of the solvent, andfor a period of time from 1 to 96 hours.

Method (h) is normally performed in a solvent (e.g. pyridine,N,N-dimethylformamide, or the like.) The reaction temperature ispreferably from 0° C. to 150° C. and the reaction time from 1 hour to 96hours.

Method (i) is normally performed in a solvent such as an alcohol (e.g.methanol or ethanol), acetone, dimethylsulfoxide, N,N-dimethylformamide,pyridine or the like in the presence of a base (e.g. an alkali metalcarbonate or a tertiary amine) or in an excess of the compound offormula XVI at a temperature from -20° C. to the boiling point of thesolvent.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the time-course of degradation of1-(N,N-dimethylglycyloxymethyl)allopurinol (o) and the concomitantformation of allopurinol (.sup.•) in a 80% human plasma solution (pH7.4) at 37° C.

FIG. 2 shows plots of the logarithm of the observed pseudo-first-orderrate constants against pH for the conversion of various allopurinolprodrugs to allopurinol in aqueous solution at 37° C.

Key: (Δ), 2,5-bis(Butyryloxymethyl)allopurinol; (o)1-(N,N-diethylglycyloxymethyl)allopurinol; and (.sup.•),1-(acetyl(allopurinol.

FIG. 3 shows mean plasma levels of oxipurinol versus time plots obtainedafter rectal administration of suppositories of allopurinol (.sup.•),1-(butryloxymethyl)allopurinol (Δ) and1-(N,N-diethylglycyloxymethyl)allopurinol hydrochloride (o) to rabbitsat a dose of 25 mg allopurinol equivalents (cross-over study involvingrabbits each weighing 2.7 kg). The plasma levels of allopurinol werebelow 1 μg/ml at all of the three blood sampling times.

FIG. 4 shows mean plasma levels of oxipurinol (o) and allopurinol(.sup.•) versus time plots obtained after rectal administration ofsuppositories of 1-(N,N-diethylglycyloxymethyl)allopurinol hydrochlorideto five human volunteers at a dose of 350 mg allopurinol equivalents.

FIG. 5 shows mean plasma levels of oxipurinol versus time plots afterintravenous administration of allopurinol (o) and1-(N,N-diethylglycyloxymethyl)allopurinol hydrochloride (.sup.•) to fourrabbits at a dose of 25 mg allopurinol equivalents. The plasma levels ofallopurinol were below 1 μg/ml at all blood sampling times.

The present invention is further illustrated by the following exampleswhich, however, are not to be construed as limiting. The examplesespecially illustrate the preferred embodiments of the invention.

Spectral and chromatographical data of the prepared compounds are givenin Table 1.

EXAMPLE 1 1-(Acetyl)allopurinol ##STR34##

A suspension of allopurinol (500 mg, 3.67 mmole) in acetic acidanhydride (8 ml) was heated in an oil bath at 130° C. for five hours.After cooling, water (10 ml) was added and the mixture was stirred atroom temperature for three hours. The precipitate was collected andwashed with water and dried, yielding 375 mg (57%). Recrystallizationfrom ethanol-N,N-dimethylformamide gave an analytically pure compound,m.p. 251°-254° C. (dec.).

EXAMPLE 2 1-(Propionyl)allopurinol ##STR35##

The compound was prepared from allopurinol and propionic acid anhydrideby the procedure described in Example 1. The yield was 60%.Recrystallization from ethanol-N,N-dimethylformamide gave ananalytically pure product, m.p. 259°-263° C.

EXAMPLE 3 1-(Butyryl)allopurinol ##STR36##

The compound was prepared from allopurinol and butyric acid anhydride bythe procedure described in Example 1. The yield was 52%.Recrystallization from ethanol gave an analytically pure product, m.p.222°-225° C.

EXAMPLE 4 1-(Chloroacetyl)allopurinol ##STR37##

A mixture of allopurinol (2.7 g; 20 mmole) and chloroacetic acidanhydride (6.8 g; 40 mmole) in N,N-dimethylformamide (20 ml) was heatedto 80° C. and a clear solution was obtained. After 1 hour, the solutionwas cooled and the precipitate was collected and washed with acetone.Yield: 2.6 g (61%), m.p. 233°-236° C. (dec.).

EXAMPLE 5 1-(Benzoyl)allopurinol ##STR38##

The compound was prepared from allopurinol and benzoic acid anhydride bythe procedure described in Example 4. The yield was 50%.Recrystallization from N,N-dimethylformamide gave an analytically purecompound, m.p. 270°-273° C. (dec.).

EXAMPLE 6 1-(Acetyloxymethyl)allopurinol ##STR39##

A mixture of 1-hydroxymethylallopurinol (1.6 g; 10 mmole) and aceticacid anhydride (2.5 ml) in pyridine (10 ml) was stirred at roomtemperature for 20 hours. The precipitate was collected, washed withethanol, and dried. Yield: 780 mg (47%), m.p. 257° C.

EXAMPLE 7 1-(Benzoyloxymethyl)allopurinol ##STR40##

A mixture of 1-hydroxymethylallopurinol (0.8 g; 5 mmole) and benzoylchloride (0.75 ml; 6.5 mmole) in pyridine (10 ml) was stirred at roomtemperature for 3 hours. Water (30 ml) was added and after standing for20 hours at 5° C., the precipitate was collected and recrystallized fromethanol. Yield: 900 mg (67%), m.p. 217°-219° C.

EXAMPLE 8 1-(Nicotinoyloxymethyl)allopurinol ##STR41##

The compound was prepared from 1-hydroxymethylallopurinol andnicotinoylchloride by essentially the same procedure as described inExample 7. After recrystallizaion from ethanol, the yield was 30%, m.p.242°-243° C.

EXAMPLE 9 1-(Chloroacetyloxymethyl)allopurinol ##STR42##

A mixture of 1-hydroxymethylallopurinol (0.83 g; 5 mmole) andchloroacetic acid anhydride (1.03 g; 6 mmole) in pyridine (20 ml) wasstirred at room temperature for 18 hours. Ethanol (20 ml) was added andthe precipitate collected, and recrystallized from ethanol. M.p.203°-205° C. (dec.).

EXAMPLE 10 1-(Butyryloxymethyl)allopurinol ##STR43##

To a suspension of 1-hydroxymethylallopurinol (1.44 g; 8.7 mmole) inmethylene chloride (100 ml) was added triethylamine (2.64 g; 26 mmole)and butyrylchloride (2.20 g; 20.8 mmole). The mixture was stirred atroom temperature for twenty hours. The resulting clear solution waswashed with water (50 ml), aqueous sodium hydrogen-carbonate (2.5%, 50ml), and water (2×50 ml). The solution was dried and evaporated. Theresidue was triturated with ethyl acetate yielding 567 mg (28%) of crudeproduct. Recrystallization from ethanol yielded an analytically purecompound, m.p. 224°-226° C.

EXAMPLE 11 1-(N,N-Dimethylglycyloxymethyl)allopurinol (hydrochloride)##STR44##

A mixture of 1-hydroxymethylallopurinol (2.0 g; 12 mmole),N,N-dimethylglycine (1.25 g; 12 mmole), N,N'-dicyclohexylcarbodiimide(2.5 g; 12 mmole), and 4-toluenesulfonic acid (150 mg) in pyridine (40ml) was stirred at room temperature for 48 hours. Methylene chloride (80ml) was added. The mixture was filtered and the filtrate was evaporatedin vacuo. The residue was extracted with two 50 ml portions of boilingmethylene chloride, and the extracts were evaporated. The residue wasrecrystallized from ethyl acetate. The crude compound obtained wassuspended in ethanol (20 ml) and a 2N solution of hydrochloric acid inethyl acetate (8 ml) was added followed by ethylacetate (20 ml). Theprecipitate was collected (1.32 g) and recrystallized frommethanol-ether yielding an analytically pure product, m.p. 203°-206° C.(dec.).

EXAMPLE 12 1-[4-(N,N-Dimethylamino)butyryloxymethyl]allopurinol(hydrochloride) ##STR45##

Using the same procedure as described in Example 11, but usingN,N-dimethyl-4-aminobutyric acid instead of N,N-dimethylglycine yieldedthe title compound, m.p. 150°-155° C. (dec.).

EXAMPLE 13 1-(DL-N,N-Diethylalanyloxymethyl)allopurinol (hydrochloride)##STR46##

The compound was prepared from 1-hydroxymethylallopurinol andDL-N,N-diethylalanine by the procedure described in Example 11. Theyield was 24%, m.p. 165°-170° C. (dec.).

EXAMPLE 14 1-(N,N-Dipropylglycyloxymethyl)allopurinol (hydrochloride)##STR47##

The compound was prepared from 1-hydroxymethylallopurinol andN,N-dipropylglycine by the procedure described in Example 11. Thecompound crystallized from ethanol 195°-198° C. (dec.).

EXAMPLE 15 1-(N,N-Diethylglycyloxymethyl)allopurinol (hydrochloride)##STR48##

A mixture of 1-hydroxymethylallopurinol (3.8 g; 16.8 mmole),N,N-diethylglycine hydrochloride (2.88 g; 17 mmole),N,N'-dicyclohexylcarbodiimide (3.6 g; 17.5 mmole), and 4-toluenesulfonicacid (270 mg) in pyridine (60 ml) was stirred at room temperature for 24hours. Methylene chloride (50 ml) was added to the reaction mixture. Theprecipitate was collected and stirred with water (15 ml). The insolublecompound was filtered off and washed with water and the combinedfiltrates were evaporated in vacuo. The residue was recrystallized twicefrom methanol-ether yielding an analytically pure compound (1.3 g; 25%),m.p. 196°-198° C. (dec.).

EXAMPLE 16 1-(DL-Alanyloxymethyl)allopurinol (hydrobromide) ##STR49##

A mixture of 1-hydroxymethylallopurinol (1.6 g; 10 mmole),N-benzyloxycarbonyl-D,L-alanine (2.23 g; 10 mmole),N,N'-dicyclohexylcarbodiimide (2.06 g; 10 mmole), and 4-toluenesulfonicacid (150 mg) in pyridine (60 ml) was stirred at room temperature for 20hours. Methylene chloride (100 ml) was added and the mixture wasfiltered. The filtrate was evaporated in vacuo and the residue wasextracted with boiling methylene chloride (3×50 ml). The methylenechloride was evaporated and the residue was recrystallized from ethylacetate-ethanol. To the crude N-protected compound was added a 33%solution of hydrobromic acid in acetic acid (8 ml). The mixture wasstirred at room temperature for seven minutes and ethyl acetate (50 ml)was added. The precipitate (520 mg, 16%) was collected andrecrystallized from methanol. The title compound was crystallized with2/3 mole of water, m.p. 195°-198° C. (dec.).

EXAMPLE 17 1-(Succinyloxymethyl)allopurinol ##STR50##

A mixture of 1-hydroxymethylallopurinol (1.6 g; 10 mmole) and succinicacid anhydride in pyridine (20 ml) was stirred at room temperature for96 hours. Hydrochloric acid 4N (50 ml) was added and the precipitate wascollected. From ethanol-N,N-dimethylformamide the title compoundcrystallized with 0.25 equivalent of water. M.p. 217°-219° C. (dec.).

EXAMPLE 18

(1) R₁ =R₅ =tert.butyloxymethyl [Method (c)]

(2) R₂ =R₅ =tert.butyloxymethyl

(3) R₁ =tert.butyloxymethyl; R₅ =hydrogen

(4) R₂ =tert.butyloxymethyl; R₅ =hydrogen

To a solution of allopurinol (2.04 g; 15 mmole) in dimethyl sulfoxide(45 ml) kept at 40° C. were added potassium carbonate (2.07 g; 15 mmole)and then dropwise during one hour a solution of chloromethyl pivalate(2.2 g; 15 mmole) in dimethyl sulfoxide (15 ml). The mixture was stirredat 40° C. for four hours and poured on ice (75 g). After acidification,the mixture was extracted with chloroform (3×70 ml). The extracts werewashed with water, dried, and evaporated. Toluene (5 ml) was added tothe residue, and the solid compound formed was collected by filtrationand washed on the filter with ether (2×5 ml). Recrystallization of thesolid from ethyl acetate gave analytically pure2-(pivaloyloxymethyl)allopurinol (813 mg; m.p. 180°-181° C.).

The toluene-ether filtrate from the crude solid was evaporated in vacuo.Column chromatography (CC) (silica gel, eluents toluene-ethylacetate-methanol) was performed on the residue, and the compounds werecollected in the following order:

(1) 1,5-bis(Pivaloyloxymethyl)allopurinol (90 mg; m.p. 136°-137° C.,recrystallized from ether-light petroleum).

(2) 2,5-bis(Pivaloyloxymethyl)allopurinol (402 mg; m.p. 145°-146° C.,recrystallized from ethyl acetate-ether-light petroleum).

(3) 1-(Pivaloyloxymethyl)allopurinol (151 mg; m.p. 185°-187° C.,recrystallized from ethyl acetate).

EXAMPLE 19

(1) R₁ =R₅ =butyloxymethyl [Method (c)]

(2) R₂ =R₅ =butyloxymethyl

(3) R₁ =butyloxymethyl; R₅ =hydrogen

(4) R₂ =butyloxymethyl; R₅ =hydrogen

By using the same procedure as described in Example 18 and equivalentamounts of allopurinol and chloromethyl butyrate, the followingcompounds were obtained:

(1) 1,5-bis(Butyryloxymethyl)allopurinol, m.p. 122°-123° C. (from ethylacetate-ether-light petroleum).

(2) 2,5-bis(Butyryloxymethyl)allopurinol, m.p. 133°-135° C. (from ethylacetate-ether-light petroleum).

(3) 1-(Butyryloxymethyl)allopurinol, m.p. 220°-225° C. (from ethylacetate).

(4) 2-(Butyryloxymethyl)allopurinol, m.p. 182°-183° C. (from ethylacetate).

EXAMPLE 20 1-(N,N-Dimethylglycyl)allopurinol (hydrochloride)

R₁ =(CH₃)₂ NCH₂ CO--; R₅ =H [Method (a)]

To a suspension of allopurinol (778 mg, 5.7 mmole) in 5 ml ofN,N-dimethylformamide was added a solution of N,N-dimethylglycinylchloride hydrochloride (5.7 mmole) in 10 ml of N,N-dimethylformamide.The mixture was heated to 80° C. for 1 hour. After cooling theprecipitate was collected and washed with ethanol. Yield: 209 mg, m.p.192°-196° C. (dec.).

EXAMPLE 21 1-(Ethoxycarbonyloxymethyl)allopurinol

R₁ =CH₃ CH₂ --O--CO--O--CH₂ --; R₅ =H [Method (b)]

The compound was prepared from 1-hydroxymethylallopurinol and ethylchloroformate by the same procedure as described in Example 7. Afterrecrystallization from ethanol the yield was 38%, m.p. 228° C.

EXAMPLE 22 1-(DL-Phenylglycyloxymethyl)allopurinol (hydrobromide)

R₁ =C₆ H₅ CH(NH₂)CO--OCH₂ --; R₅ =H [Method (b)]

The compound was prepared from 1-hydroxymethylallopurinol andN-(benzyloxycarbonyl)-DL-phenylglycine by the procedure described inExample 16. The analytically pure title compound crystallized frommethanol-ether, m.p. 192°-195° C. (dec.).

EXAMPLE 23 2,5-bis(Butyryloxymethyl)allopurinol ##STR51##

A mixture of 400 mg of 2,5-dihydroxymethylallopurinol (prepared asdescribed by Bansal et al. (1981), where the compound is designated1,5-[bis(hydroxymethyl)]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one),butyric acid anhydride (1 ml), and pyridine (5 ml) was stirred at roomtemperature for 24 hours. Water (20 ml) was added to the solution andafter stirring for 2 hours the precipitate was collected.Recrystallization from ethyl acetate afforded 268 mg of the titlecompound, which had the same m.p. and spectral data as the compoundsynthesized according to Example 19.

EXAMPLE 24 2,5-bis(Acetoxymethyl)allopurinol ##STR52##

The compound was prepared from 2,5-dihydroxymethylallopurinol and aceticacid anhydride by the procedure described in Example 23.Recrystallization from ethanol gave an analytically pure product in ayield of 68%, m.p. 153°-154° C.

EXAMPLE 25 2,5-bis-(DL-Alanyloxymethyl)allopurinol (dihydrobromide)##STR53##

The compound was prepared from 2,5-dihydroxymethylallopurinol and thedouble amounts of N-(benzyloxycarbonyl)-D,L-alanine,N,N'-dicyclohexylcarbodiimide, and pyridine by essentially the sameprocedure as described in Example 16. Recrystallization frommethanol-ethyl acetate-ether yielded 16% of the title compound, m.p.190°-192° C. (dec.). The compound crystallized with 0.5 mole ofmethanol.

EXAMPLE 26 1-[4-(N,N-Dimethylamino)butyryl]allopurinol (hydrochloride)##STR54##

The compound was prepared from allopurinol and 4-(N,N-dimethyl)butyrylchloride hydrochloride by the same procedure as described in Example 20.The compound crystallized with 1/3 mole of water and did not melt below270° C.

EXAMPLE 27 1-(DL-Phenylalanyloxymethyl)allopurinol (hydrobromide)##STR55##

The compound was prepared from 1-hydroxymethylallopurinol andN-(benzyloxycarbonyl)-DL-phenylalanine by the procedure described inExample 16. The analytically pure title compound crystallized with 1/4mole of water from methanol, m.p. 204°-205° C. (dec.).

EXAMPLE 28 1-(L-Leucyloxymethyl)allopurinol (hydrobromide) ##STR56##

The compound was prepared from 1-hydroxymethylallopurinol andN-(benzyloxycarbonyl)-L-leucine by essentially the same procedure asdescribed in Example 16. The analytically pure title compoundcrystallized from methanol-acetonitrile with 1 mole of water, m.p.215°-217° C. (dec.).

EXAMPLE 29 1-(N-Butylcarbamoyl)allopurinol ##STR57##

A mixture of allopurinol (2.7 g, 20 mmole), triethylamine (0.2 ml),butylisocyanate (3 g, 30 mmole) in N,N-dimethylformamide was stirred at90° C. for 2 hours. Upon cooling 1.05 g of the title compoundprecipitated. The crude product was recrystallized fromN,N-dimethylformamide-ethanol, m.p.>270° C.

EXAMPLE 30 1-[3-(N,N-Diethylcarbamoyl)propionyloxymethyl]allopurinol##STR58##

A mixture of 1-hydroxymethylallopurinol (1.47 g; 8.8 mmole),3-(N,N-diethylcarbamoyl)propionic acid (1.53 g; 8.8 mmole),N,N'-dicyclohexylcarbodiimide (1.8 g; 8.8 mmole), and 4-toluenesulfonicacid (100 mg) in pyridine (30 ml) was stirred at room temperature for 24hours. Methylene chloride (60 ml) was added, the mixture was filtered,and the filtrate evaporated in vacuo. The residue was extracted withwarm methylene chloride (50 ml) and the methylene chloride wasevaporated. The residue was recrystallized from ethyl acetate yielding0.71 g (25%); m.p. 128°-131° C.

EXAMPLE 31 1-(Glycyloxymethyl)allopurinol (hydrochloride) ##STR59##

The compound was prepared from 1-hydroxymethylallopurinol andN-(tert.butyloxycarbonyl)glycine by the same procedure as described inExample 16. The tert.butyloxycarbonyl-protecting group was removed with1N hydrochloric acid. The title compound melted at 192°-195° C. (dec.).

                                      TABLE 1                                     __________________________________________________________________________    .sup.1 H NMR and UV spectral data, and HPLC chromatographic                   capacity factors of various allopurinol prodrugs                                                     .sup.λ max.sup.(nm)                                                          Chromatographic                                                 .sup.1 H NMR (δ)                                                                (in pH 5.0                                                                          capacity                                         Compound       H(3) and H(6)                                                                         buffer)                                                                             factor (k')                                      __________________________________________________________________________    1-(Acetyl)allopurinol.sup.a                                                                  8.30                                                                              8.38                                                                              274   1.05.sup.c                                       1-(Propionyl)allopurinol.sup.a                                                               8.30                                                                              8.37                                                                              274   0.66.sup.d                                       1-(Butyryl)allopurinol.sup.a                                                                 8.32                                                                              8.40                                                                              274   1.10.sup.d                                       1-(Benzoyl)allopurinol.sup.a                                                                 8.32                                                                              8.46                                                                              250,280(sh)                                                                         1.20.sup.d                                       1-(Chloroacetyl)allopurinol.sup.a                                                            8.29                                                                              8.39                                                                              274   n.d.                                             1-(Acetyloxymethyl)allo-                                                                     8.20                                                                              8.22                                                                              251   0.30.sup.d                                       purinol.sup.a                                                                 1-(Butyryloxymethyl)allo-                                                                    8.20                                                                              8.23                                                                              251   0.85.sup.d                                       purinol.sup.a                                                                 1-(Pivaloyloxymethyl)allo-                                                                   8.19                                                                              8.23                                                                              251   1.50.sup.d                                       purinol.sup.a                                                                 1-(Benzoyloxymethyl)allo-                                                                    8.45                                                                              8.49                                                                              234   2.00.sup.d                                       purinol.sup.a                                                                 1-(Nicotinoyloxymethyl)allo-                                                                 8.41                                                                              8.48                                                                              251   0.67.sup.d                                       purinol.sup.a                                                                 1-(Chloroacetoxymethyl)-                                                                     8.31                                                                              8.33                                                                              251   n.d.                                             allopurinol.sup.a                                                             1-(DL-Alanyloxymethyl)-                                                                      8.38                                                                              8.42                                                                              251   1.37.sup.c                                       allopurinol.sup.b                                                             1-(DL-N,N--Diethylalanyloxy-                                                                 8.36                                                                              8.45                                                                              251   17.1.sup.c                                       methyl)allopurinol.sup.b                                                      1-(N,N--Dimethylglycyl-                                                                      8.28                                                                              8.34                                                                              251   4.00.sup.c                                       oxymethyl)allopurinol.sup.b                                                   1-(N,N--Diethylglycyl-                                                                       8.27                                                                              8.32                                                                              251   12.0.sup.c                                       oxymethyl)allopurinol.sup.b                                                   1-(N,N--Dipropylglycyl-                                                                      8.34                                                                              8.40                                                                              251   >60.sup.c                                        oxymethyl)allopurinol.sup.b                                                   1-[4-(N,N--Dimethylamino)-                                                                   8.29                                                                              8.35                                                                              251   n.d.                                             butyryloxymethyl]allopuri-                                                    nol.sup.b                                                                     2-(Butyryloxymethyl)allo-                                                                    8.06                                                                              8.78                                                                              261   0.65.sup.d                                       purinol.sup.a                                                                 2-(Pivaloyloxymethyl)allo-                                                                   8.08                                                                              8.70                                                                              261   1.07.sup.d                                       purinol.sup.a                                                                 1,5-bis(Butyryloxymethyl)-                                                                   8.28                                                                              8.62                                                                              251   4.82.sup.d                                       allopurinol.sup.a                                                             1,5-bis(Pivaloyloxymethyl)-                                                                  8.29                                                                              8.64                                                                              251   13.8.sup.d                                       allopurinol.sup.a                                                             2,5-bis(Butyryloxymethyl)-                                                                   8.40                                                                              8.82                                                                              259   3.37.sup.d                                       allopurinol.sup.a                                                             2,5-bis(Pivaloyloxymethyl)-                                                                  8.41                                                                              8.85                                                                              259   9.9.sup.d                                        allopurinol.sup.a                                                             1-(N,N--Dimethylglycyl)-                                                                     8.45                                                                              8.46                                                                              279   n.d.                                             allopurinol.sup.b                                                             1-(Glycyloxymethyl)allo-                                                                     8.27                                                                              8.32                                                                              251   0.89.sup.c                                       purinol.sup.b                                                                 1-(Ethoxycarbonyloxy-                                                                        8.24                                                                              8.28                                                                              251   n.d.                                             methyl)allopurinol.sup.a                                                      1-(DL-Phenylglycyloxy-                                                                       8.15                                                                              8.20                                                                              n.d.  n.d.                                             methyl)allopurinol.sup.b                                                      1-(Succinyloxymethyl)-                                                                       8.23                                                                              8.25                                                                              251   n.d.                                             allopurinol.sup.a                                                             2,5-bis(Acetyloxymethyl)-                                                                    8.70                                                                              9.17                                                                              259   n.d.                                             allopurinol.sup.a                                                             2,5-bis(DL-Alanyloxymethyl)-                                                                 8.51                                                                              8.97                                                                              259   n.d.                                             allopurinol.sup.b                                                             1-(L-Leucyloxymethyl)-                                                                       8.32                                                                              8.36                                                                              251   0.80.sup.d                                       allopurinol.sup.b                                                             1-(DL-Phenylalanyloxy-                                                                       8.28                                                                              8.30                                                                              251   1.05.sup.d                                       methyl)allopurinol.sup.b                                                      __________________________________________________________________________     .sup.a NMR in DMSOd.sub.6                                                     .sup.b NMR in D.sub.2 O                                                       .sup.c Mobile phase: 0.02 M phosphate buffer pH 7.4  methanol (4:1 v/v)       .sup.d Mobile phase: 0.01 M acetate buffer pH 4.5  methanol (1:1 v/v)         Column: 250 mm × 4 mm LiChrosorb RP8 (Merck)                            n.d. = Not determined                                                    

In-vitro cleavage of allopurinol derivatives

Reaction conditions.

Solutions of various derivatives of allopurinol in aqueous buffersolutions or 80% human plasma solutions (pH 7.4) were kept at 37° C. Theinitial concentration of the derivatives was in the range 0.01-0.1mg/ml. At various times an aliquot of the solutions was withdrawn andanalyzed by HPLC for remaining derivative as well as for allopurinol.For the plasma solutions the aliquot withdrawn was deproteinized withethanol or trichloroacetic acid and after centrifugation, the clearsupernatant was injected on HPLC.

Analytical method.

An HPLC method was used for the determination of allopurinol and itsderivatives. In this method a reversed-phase LiChrosorb RP-8 column(250×4 mm) was eluated at ambient temperature with mixtures of methanoland 0.01M acetate buffer pH 4.5 or methanol and 0.03M phosphate bufferpH 7.0. The composition of the eluant was adjusted for each compound inorder to provide an appropriate retention time. The flow rate was 1.2ml/min and the column effluent was monitored spectrophotometrically at252 nm or 274 nm. Quantitation of the compounds was done by measurementof peak heights.

A complete conversion of the derivatives to allopurinol was found totake place and in all cases, the cleavage of the derivatives displayedstrict first-order kinetics. An example is shown in FIG. 1. The rate ofhydrolysis varied greatly with pH of the solutions as illustrated inFIG. 2, showing the pH-rate profiles for some of the derivatives.

The half-times of allopurinol formation from various derivatives atphysiological conditions of pH and temperature are given in Table 2. Itcan be seen that in the presence of human plasma the rate of degradationis strongly accelerated, thus showing the susceptibility of thederivatives to undergo conversion into the parent active compound atconditions simiar to those prevailing in vivo.

The water-solubility and lipophilicity of the allopurinol drugs

The apparent partition coefficients (P) for some allopurinol derivativesand allopurinol were measured using the widely used 1-octanol-watersystem. Similarly, the solubility of the derivatives in water or aqueousbuffer solutions was determined. The values found for log P and thewater-solubilities are listed in Table 3. The results obtained showclearly that by varying the pro-moieties of the derivatives or the typeof derivative it is feasible to obtain prodrugs of allopurinol withvarying and any desirable lipophilicity or water solubility. Thus, asdemonstrated with the compound 1-(N,N-diethylglycyloxymethyl)allopurinolhydrochloride it is possible to obtain a prodrug form which at the sametime possesses both a much higher aqueous solubility (i.e. a factor5,000) and a higher lipophilicity than the parent compound.

Bioavailability of some allopurinol derivatives and allopurinolfollowing rectal administration

Suppositories were prepared of allopurinol and some derivatives of thepresent invention using Adepes solidus (Ph. Nord. 63) as the suppositorybase. Each suppository contained an amount of the appropriate compound(brought to the same particle size by sieving) equivalent to 25 mg ofallopurinol. Some water-soluble derivatives were also formulated asmicro-enemas, the solvent being a 0.5% aqueous solution ofmethylcellulose. The suppositories or micro-enemas were administered torabbits. After drug administration, blood samples were taken at varioustimes and the plasma fraction assayed for allopurinol and its majormetabolite oxipurinol using the HPLC method described above.

FIG. 3 shows some representative plots of plasma oxipurinolconcentrations versus time following rectal administration to rabbits.The results clearly demonstrate that the allopurinol derivatives exhibita greatly enhanced bioavailability as compared with allopurinol whichshowed only a very low degree of absorption (<2% of the dose given). Theplasma samples were also analyzed for intact allopurinol prodrugs but inall cases no measurable concentrations (<0.1 μg/ml) were observed. Thus,it is evident from the results that allopurinol prodrug forms of thepresent invention provide an efficient absorption of allopurinol afterrectal administration in sharp contrast to the behaviour of allopurinolper se. Moreover, the above studies demonstrate that the prodrugs areconverted back to allopurinol in vivo in accordance with the "prodrug"definition provided at the outset of this application.

In addition to these animal experiments, a micro-enema preparation ofthe hydrochloride salt of 1-(N,N-diethylglycyloxymethyl)allopurinol wasadministered to a healthy human volunteer. The dose given (2 ml of a0.5% methylcellulose solution containing 118 mg/ml of the prodrug)corresponded to 100 mg of allopurinol. Urine was collected over 5 daysand aliquots were assayed for allopurinol and oxipurinol by a specificHPLC assay. The total urinary excretion of allopurinol and oxipurinolwas found to be 11 and 78 mg, respectively. Since it is known(Breithaupt & Tittel, 1982) that about 88% of a dose of allopurinoladministered intravenously are recovered in the urine in the form ofintact allopurinol (12%) and oxipurinol (76%) the result of theexperiment indicates a virtually complete bioavailability of the parentdrug from the prodrug derivative given rectally.

Furthermore, suppositories containing the hydrochloride salt of1-(N,N-diethylglycyloxymethyl)allopurinol in an amount equivalent to 350mg of allopurinol and made using Adeps solidus as the suppository basewere administered rectally to five healthy human volunteers. After drugadministration, blood samples were taken at various times and the plasmafraction assayed for allopurinol and oxipurinol by means of HPLC. FIG. 4shows the average plasma data obtained. The same volunteers were alsogiven a tablet preparation of allopurinol and from the plasma dataobtained, the bioavailability of the suppository preparation containingthe allopurinol prodrug was estimated to be 42% of that of the oralpreparation.

Bioavailability after parenteral and oral administration

An aqueous solution of 1-(N,N-diethylglycyloxymethyl)allopurinolhydrochloride (1 ml containing 59 mg of the compound ˜25 mg ofallopurinol) was given intravenously to four rabbits. FIG. 5 shows themean plasma oxipurinol concentration vs. time curve obtained along withthe plasma concentration vs. time data observed after similaradministration of 25 mg of allopurinol to the form of a 1% alkalinesolution of sodium salt. The results of the experiment indicates analmost complete bioavailability of the parent drug from the prodrugderivative given intravenously.

A comparative absorption study was also made of allopurinol and theabove mentioned prodrug following peroral administration. Each compoundwas given to a healthy human volunteer in a dose corresponding to 100 mgallopurinol, allopurinol in the form of a commercially available tabletand 1-(N,N-diethylglycyloxymethyl)allopurinol hydrochloride as asolution in water (236 mg in 10 ml). The total urinary excretion ofallopurinol and oxipurinol was measured and found to correspond to 67%of the dose given for the allopurinol tablet and 92% for the preparationcontaining the prodrug derivative.

                  TABLE 2                                                         ______________________________________                                        Half-times (t.sub.0.5) of the conversion of various allopurinol               derivatives to allopurinol at 37° C.                                                      t.sub.0.5                                                                       pH 7.4    80% human                                      Compound             buffer    plasma, min                                    ______________________________________                                        1-(Butyryloxymethyl)allopurinol                                                                    193    h      9                                          2-(Butyryloxymethyl)allopurinol                                                                    54     h      22                                         1,5-bis(Butyryloxymethyl)allopurinol                                                               25     h      22                                         2,5-bis(Butyryloxymethyl)allopurinol                                                               35     h      32                                         1-(Acetoxymethyl)allopurinol                                                                       87     h      31                                         2,5-bis(Acetoxymethyl)allopurinol                                                                  15     h      51                                         1-(Benzoyloxymethyl)allopurinol                                                                    237    h      4                                          1-(Nicotinoyloxymethyl)allopurinol                                                                 26     h      21                                         1-(Glycyloxymethyl)allopurinol                                                                     26     min    9                                          1-(N,N--Dimethylglycyloxymethyl)-                                                                  72     min    7                                          allopurinol                                                                   1-(N,N--Diethylglycyloxymethyl)-                                                                   49     min    10                                         allopurinol                                                                   1-(DL-N,N--Diethylalanyloxymethyl)-                                                                21     min    17                                         allopurinol                                                                   1-(Acetyl)allopurinol                                                                              26     min    6                                          1-(Propionyl)allopurinol                                                                           30     min    4                                          1-(Butyryl)allopurinol                                                                             36     min    2.5                                        1-(Benzoyl)allopurinol                                                                             20     min    4                                          l-(DL-Alanyloxymethyl)allopurinol                                                                  15     min    11                                         1-(N,N--Dipropylglycyloxymethyl)-                                                                  50     min    12                                         allopurinol                                                                   1-(DL-Phenylglycyloxymethyl)                                                                       20     min    3                                          allopurinol                                                                   1-(L-Leucyloxymethyl)allopurinol                                                                   17     min    6                                          1-(Ethoxycarbonyloxymethyl)                                                                        --        20                                             allopurinol                                                                   1-(N,N--Dimethylglycyl)-                                                                           1.5    min    <1                                         allopurinol                                                                   1-(N--Butylcarbamoyl)-                                                                             --        90                                             allopurinol                                                                   1-(DL-Phenylalanyloxymethyl)-                                                                      40     min    9                                          allopurinol                                                                   1[3-(N,N--Diethylcarbamoyl)-                                                                       81     h      8.4 h                                      propionyloxymethyl]allopurinol                                                1-(Chloroacetyl)allopurinol                                                                        <1     min    <1                                         1[4-(N,N--Dimethylamino)-                                                                          145    min    140                                        butyryloxymethyl]allopurinol                                                  2,5-bis(DL-Alanyloxymethyl)-                                                                       <1     min    < 1                                        allopurinol                                                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Water-solubilities (S) and partition coefficients (P) -for allopurinol        and various allopurinol prodrugs.                                                                   S.sup.a                                                 Compound              (mg/ml)  log P.sup.b                                    ______________________________________                                        Allopurinol           0.50     -0.55                                          1-(Pivaloyloxymethyl)allopurinol                                                                    0.52     1.07                                           2-(Pivaloyloxymethyl)allopurinol                                                                    1.7      0.79                                           1,5-bis(Pivaloyloxymethyl)allopurinol                                                               0.02     2.50                                           2,5-bis(Pivaloyloxymethyl)allopurinol                                                               0.045    2.34                                           1-(Butyryloxymethyl)allopurinol                                                                     0.35     0.60                                           2-(Butyryloxymethyl)allopurinol                                                                     1.5      0.33                                           1,5-bis(Butyryloxymethyl)allopurinol                                                                0.050    1.82                                           2,5-bis(Butyryloxymethyl)allopurinol                                                                0.094    1.60                                           1-(Acetoxymethyl)allopurinol                                                                        0.58     -0.35                                          2,5-bis(Acetoxymethyl)allopurinol                                                                   2.9      n.d.                                           1-(Benzoyloxymethyl)allopurinol                                                                     0.024    1.50                                           1-(Nicotinoyloxymethyl)allopurinol                                                                  0.093    0.27                                           1-(Glycycloxymethyl)allopurinol                                                                     >500     n.d.                                           hydrochloride                                                                 1-(DL-Alanyloxymethyl)allopurinol                                                                   >500     n.d.                                           hydrobromide                                                                  1-(N,N--Dimethylglycyloxymethyl)-                                                                   >500     -0.49.sup.c                                    allopurinol hydrochloride                                                     1-(N,N--Diethylglycyloxymethyl)-                                                                    >500     0.20.sup.c                                     allopurinol hydrochloride                                                     1-(N,N--Dipropylglycyloxymethyl)-                                                                   >400     1.27.sup.c                                     allopurinol hydrochloride                                                     1-(DL-N,N--Diethylalanyloxymethyl)-                                                                 >400     0.72.sup.c                                     allopurinol hydrochloride                                                     1-(DL-Phenylglycyloxymethyl)                                                                        >200     -0.15.sup.c                                    allopurinol hydrobromide                                                      1-(Acetyl)allopurinol 0.75     -0.35                                          1-(Propionyl)allopurinol                                                                            0.30     0.30                                           1-(Butyryl)allopurinol                                                                              0.11     0.85                                           1-(Benzoyl)allopurinol                                                                              0.014    1.20                                           1-(Ethoxycarbonyloxymethyl)-                                                                        n.d.     0.21                                           allopurinol                                                                   1-(DL-Phenylalanyloxymethyl)-                                                                       >200     0.40.sup.c                                     allopurinol hydrobromide                                                      1-(L-Leucyloxymethyl)allopurinol                                                                    >400     0.19.sup.c                                     hydrobromide                                                                  1-[3-N,N--Diethylcarbamoyl)-                                                                          33     -0.22                                          propionyloxymethyl]allopurinol                                                1-(N,N--Dimethylglycyl)allopurinol                                                                  >200     n.d.                                           hydrochloride                                                                 ______________________________________                                         .sup.a At 21 ± 1°  C.                                               .sup.b Between octanol and water                                              .sup.c Between octanol and a borate buffer pH 8.0                             n.d. = not determined                                                    

References Cited

Appelbaum, S. J., M. Mayersohn, D. Perrier & R. T. Dorr: Drug Intell.Clin. Pharm. 14, (1980), p. 789.

Appelbaum, S. J. Mayersohn, R. T. Dorr & D. Perrier: Cancer Chemother.Pharmacol. 8, (1982), p. 93.

Bansal, P. C., I. H. Pitman & T. Higuchi: J. Pharm. Sci. 70, (1981), p.855.

Bergmann, F., Frank, A. & Neimann, Z.: J. Chem. Soc. Perkin Trans I,(1979), p. 2795.

Breithaupt, H. & M. Tittel: Eur. J. Clin. Pharmacol. 22, (1982), p. 77.

Bundgaard, H. & M. Johansen: Acta Pharm. Suec 18, (1981), p. 129.

Chang, S.-L., W. G. Kramer, S. Feldman, R. Ballentine & L. S. Frankel:Am. J. Hosp. Pharm. 38, (1981), p. 365.

Elion, G. B., A. Kovinsky, G. H. Hitchings, E. Metz & R. W. Rundles:Biochem. Pharmacol. 15, (1966), p. 863.

Elion, G. B.: Handbook Exp. Pharmacol. 51, (1978), p. 485.

Hussain, A. & J. H. Rytting: J. Pharm. Sci. 63, (1974), p. 798.

De Leede, L. G. J. & A. G. De Boer: Biopharm. Drug Disp. 2, (1981), p.131.

De Leede, L. G. J., A. G. De Boer, S. L. van Velzen & D. D. Breimer: J.Pharmacokin, Biopharm. 10, (1982), p. 525.

"Remington's Pharmaceutical Sciences", Sixteenth Edition (1980), MackPublishing Company, Easton.

Spector, T.: Biochem. Pharmacol. 26, (1977), p. 355. P & V F3449A jA423449 PCT HRA/BM 1984 05 16

We claim:
 1. A compound of the formula Ia or Ib ##STR60## wherein R₁ isa group of the formula II ##STR61## wherein R₃ is C₁₋₈ alkyl; C₁₋₄ alkylmonosubstituted with chloro or bromo; phenyl; phenyl substituted with1-3 substituents selected from chloro, bromo, C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, acetoxy, or phenoxy; phenyl C₁₋₄ alkyl in which the phenyl groupmay be substituted with 1-3 substituents selected from chloro, bromo,C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, acetoxy or phenoxy; or phenyl C₁₋₄alkenyl in which the phenyl group may be substituted with 1-3substituents selected from chloro, bromo, C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, acetoxy, or phenoxy; or R₃ is an aromatic 5- or 6-memberedheterocyclic ring selected from pyridinyl, thienyl, thiazolyl, oxazolyl,imidazolyl, isoxazolyl, isothiazolyl, furanyl and pyrimidinyl; and A isa single bond or a group of the formula IIa ##STR62## wherein the carbonatom is attached to the nitrogen atom of the parent ring system, andwherein R₆ and R₇ are the same or different and each represent hydrogenor have the same meaning as R₃ as defined above;or R₁ is a group of theformula III ##STR63## wherein R₈ and R₉ are the same or different andeach represent hydrogen or have the same meaning as R₃ as defined above;or R₈ and R₉ together with the adjacent nitrogen form a 5- or 6-memberedheterocyclic ring selected from piperidinyl, imidazolyl, pyrazolyl andpiperazinyl; Y is a group of the formula IIIa ##STR64## wherein n is aninteger from 1 to 5; and A, R₆, and R₇ are as defined above; or R₁ is agroup of the formula IV ##STR65## wherein A is as defined above and R'₃has the same meaning as R₃ defined above, with the proviso that R'₃ isnot ethyl when A is a bond; or R₁ is a group of the formula VII##STR66## wherein n and A are as defined above, and R₁₃ is hydroxy or agroup of the formula --NR₈ R₉ wherein R₈ and R₉ are as defined above; R₂is any of the groups II, III, IV and VII as defined above with theproviso that A solely is the group IIa as defined above; and R₅ ishydrogen or has the same meaning as R₂ as defined above, or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R₁ and R₅ are the same; or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 2, wherein R₁and R₅ are groups of the formulas II or III, wherein A is a group offormula IIa and Y is a group of formula IIIa; or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 1, wherein R₅is hydrogen and R₁ is a group of the formulas II, III, IV or VII; or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 4, wherein R₁ is a group of the formulas II or III wherein Y is agroup of formula IIIa or VII; or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 5, wherein A is a group offormula IIa; or a pharmaceutically acceptable salt thereof.
 7. Acompound according to claim 6, wherein R₁ is a group of the formula IIIwherein A is a group of formula IIa and Y is a group of formula IIIa; ora pharmaceutically acceptable salt thereof.
 8. A compound according toclaim 7, wherein R₁ is N,N-dimethylglycyloxymethyl,N,N-diethylglycyloxymethyl, N,N-dipropylglycyloxymethyl,N,N-dimethylalanyloxymethyl, N,N-diethylalanyloxymethyl,phenylalanyloxymethyl, phenylglycyloxymethyl, or leucyloxymethyl; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1, wherein R₂ and R₅ are the same; or a pharmaceuticallyacceptable salt thereof.
 10. A compound according to claim 9, wherein R₂and R₅ are groups of the formula III wherein A is a group of formula IIaand Y is a group of formula IIIa; or a pharmaceutically acceptable saltthereof.
 11. A compound according to claim 1, wherein R₅ is hydrogen andR₂ is a group of the formula II wherein A is a group of formula IIa; ora pharmaceutically acceptable salt thereof.
 12. A compound according toclaim 1, selected from the group consisting of1-(butyryloxymethyl)allopurinol,1-(N,N-dimethylglycyloxymethyl)allopurinol,1-(N,N-diethylglycyloxymethyl)allopurinol,1-(N,N-dipropylglycyloxymethyl)allopurinol,1-(DL-N,N-dimethylalanyloxymethyl)allopurinol,1-(DL-N,N-diethylalanyloxymethyl)allopurinol,1-(L-phenylalanyloxymethyl)allopurinol,1-(L-leucyloxymethyl)allopurinol, 1-(L-valyloxymethyl)allopurinol and1-(DL-N,N-dimethylphenylalanyloxymethyl)allopurinol; or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition for rectal, parenteral, or oral use in the prevention andtreatment of hyperuricemic states such as gout comprising apharmaceutically acceptable carrier or excipient in combination with acompound of the formula I'a or Ib ##STR67## wherein R₁ is a group of theformula II ##STR68## wherein R₃ is C₁₋₈ alkyl; C₁₋₄ alkylmonosubstituted with chloro or bromo; phenyl; phenyl substituted with1-3 substituents selected from chloro, bromo, C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, acetoxy, or phenoxy; phenyl C₁₋₄ alkyl in which the phenyl groupmay be substituted with 1-3 substituents selected from chloro, bromo,C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, acetoxy or phenoxy; or phenyl C₁₋₄alkenyl in which the phenyl group may be substituted with 1-3substituents selected from chloro, bromo, C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, acetoxy, or phenoxy; or R₃ is an aromatic 5- or 6-memberedheterocyclic ring selected from pyridinyl, thienyl, thiazolyl, oxazolyl,imidazolyl, isoxazolyl, isothiazolyl, furanyl and pyrimidinyl; and A isa single bond or a group of the formula IIa ##STR69## wherein the carbonatom is attached to the nitrogen atom of the parent ring system, andwherein R₆ and R₇ are the same or different and each represent hydrogenor have the same meaning as R₃ as defined above;or R₁ is a group of theformula III ##STR70## wherein R₈ and R₉ are the same or different andeach represent hydrogen or have the same meaning as R₃ as defined above;or R₈ and R₉ together with the adjacent nitrogen form a 5- or 6-memberedheterocyclic ring selected from piperidinyl, imidazolyl, pyrazolyl andpiperazinyl; Y is a group of the formula IIIa ##STR71## wherein n is aninteger from 1 to 5; and A, R₆, and R₇ are as defined above; or R₁ is agroup of the formula IV ##STR72## wherein A is as defined above and R'₃has the same meaning as R₃ defined above; or R₁ is a group of theformula VII ##STR73## wherein n and A are as defined above, and R₁₃ ishydroxy or a group of the formula --NR₈ R₉ wherein R₈ and R₉ are asdefined above; R₂ is any of the groups II, III, IV, and VII as definedabove with the proviso that A solely is the group IIa as defined above;and R₅ is hydrogen or has the same meaning as R₂ as defined above; or apharmaceutically acceptable salt thereof.
 14. A method for treating andpreventing hyperuricemic states comprising administering an amounteffective in lowering the level of uric acid, of a compound according toany one of claims 1-12 to a warm-blooded animal.
 15. A method fortreating and preventing hyperuricemic states comprising administering anamount effective in lowering the level of uric acid of the compositionof claim 13 to a warm-blooded animal.
 16. The method of claim 15,wherein said composition is administered orally.
 17. The method of claim15, wherein said composition is administered rectally.